Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C3=CCN(Cc4ccccc4)CC3)ccc2c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 92.2 %

Procedure:
A mixture of 2.92 gm 1-benzyl-4-(6-methoxynaphth-2-yl)-1,2,3,6-tetrahydropyridine and 0.3 gm platinum oxide in 50 mL tetrahydrofuran and 50 mL ethyl acetate was hydrogenated at room temperature for 16 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide 2.71 gm of the title compound as a white solid.
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[C:5]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1.[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][CH2:3][C:4]1[C:5]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)CCc1cc2c(cc1CCl)OCO2
Agent: [Na]
Product: CCOCc1cc2c(cc1CCC(=O)O)OCO2
Temperature: 50 °C

Procedure:
0.6 g of metallic sodium was dissolved in 100 ml of ethanol. 2.0 g of 3-(6-chloromethyl-1,3-benzodioxole-5-yl)propionic acid was added in small portions to the solution. The mixture was heated at 50° C. for 2 h. The solvent was distilled off and the residue was acidified with 1N hydrochloric acid. After extraction with chloroform, the organic layer was dried over magnesium sulfate. The solvent was distilled off. After separation according to silica gel column chromatography (chloroform), 0.73 g of the intended compound in the form of colorless crystals was obtained.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[C:10](=[S:12])=[S:11].[OH-].[K+].Cl/[CH:16]=[CH:17]\Cl>O.C(Cl)(Cl)Cl.CN(C)C=O>[S:11]1[CH:17]=[CH:16][S:12][C:10]1=[CH:1][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3]
Reactant: Cl/C=C\Cl
Reactant: COC(=O)CS(C)(=O)=O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CS(=O)(=O)C=C1SC=CS1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a mixture of 15.2 g of methyl methylsulfonylacetate, 7.6 g of carbon disulfide and 200 ml of dimethylformamide, 14.0 g of potassium hydroxide was added under ice-cooling. The resultant mixture was stirred for 3 hours. Thereafter, 9.7 g of cis-1,2-dichloroethylene was added, followed by stirring at 80° C. for 4 hours. After cooling the reaction mixture, chloroform and water were added and the resulting organic layer was separated. Upon removal of the solvent by distillation under reduced pressure, 20.9 g of the title compound was obtained as pale yellow crystals. Upon recrystallization from a mixed solvent of chloroform and n-hexane, they turned to white crystals. Melting point: 166°-168° C. (decomposed).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C@@H:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]([CH2:24][OH:25])[CH2:14][N:13]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.CC1(C)N([O])C(C)(C)CCC1.C(O)(=[O:47])C.C(O)(=O)C.IC1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:22]2[C:23]3[C:10]([CH2:11][C@@H:12]4[C@@H:17]([C:18]=3[CH:19]=[CH:20][CH:21]=2)[CH2:16][C@@H:15]([C:24]([OH:47])=[O:25])[CH2:14][N:13]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]21
Reactant: CC(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.7 %

Procedure:
To a solution of 1,6-di-(tert-butoxycarbonyl)-8β-hydroxymethyl-ergoline (328 g) in dichloromethane (1.97 L) and water (13.5 g) is added TEMPO (22.2 g). The solution is cooled using a ice-bath and iodobenzene diacetate (597 g) is added in portions. The mixture is stirred at room temperature for 12-16 h and the reaction is monitored by TLC. The reaction is quenched with the addition of sodium thiosulfate solution (184 g in 1315 mL of water), and the organic layer is separated. The aqueous is extracted with dichloromethane (656 mL) and the combined dichloromethane layers are washed with water and then evaporated to remove the solvent. The product is crystallized from cold methanol to furnish 1,6-di-(tert-butoxycarbonyl)-ergoline-8β-carboxylic acid (334 g) in 88.5% yield.
Reaction SMILES: CS(C)=O.[NH2:5][C@@:6]1([C:26]#[N:27])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-:29].[K+].[K+].OO>O>[NH2:5][C@@:6]1([C:26]([NH2:27])=[O:29])[C@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:10][C@@H:9]2[C@H:7]1[C@@:8]2([F:25])[C:22]([NH2:24])=[O:23]
Reactant: O=C([O-])[O-]
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Reaction time: 0.5 h
Yield: 324.1 %

Procedure:
To a dimethyl sulfoxide (1.2 mL) solution containing 303.0 mg of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide (6a), 35.5 mg of potassium carbonate was added under cooling in water bath (13° C. approximately). Subsequently, 0.2 mL of 30 wt % hydrogen peroxide was added thereto and stirred for 30 min. After stirring for 67.5 hrs at room temperature, 3 mL of water was added to the reaction solution and the precipitated solids were filtered and washed with 1.2 mL of water. The resulting solids were dried under reduced pressure at room temperature to obtain 313.2 mg of (1R, 2R,3R,5R,6R)-2-amino-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxamide (7a) as a colorless solid.
Reaction SMILES: C([O:4][N:5]([CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[CH:23]=1)[CH3:10])[C:6](=[O:8])[CH3:7])(=O)C.C(OC(=O)C)(=O)C.NO.C(N(CC)CC)C>C(Cl)Cl>[OH:4][N:5]([CH:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[CH:23]=1)[CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)ON(C(C)=O)C(C)c1ccc2c(c1)oc1ccccc12
Agent: NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(O)C(C)c1ccc2c(c1)oc1ccccc12
Reaction time: 8 h

Procedure:
N-acetoxy-N-(1-dibenzofur-3-ylethyl) acetamide. Acetic anhydride (9.0 mL) was added to a solution of the crude hydroxylamine, prepared as in step c, and triethyl amine (12.4 mL) in methylene chloride (50 mL). The reaction was stirred overnight, then washed with cold water and 3 N HCl. The methylene chloride layer was dried (Na2SO4) and concentrated to give a yellowish oil. This residue was chromatographed on 100 g of silica gel, eluting with 20% ethyl acetate in hexanes to give the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:18])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:39])[N:22]([C:27]2[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=2)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=1.CCN(C(C)C)C(C)C>O1CCOCC1.Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:20]2[C:21](=[O:39])[N:22]([C:27]3[C:28]([CH3:38])=[CH:29][C:30]([F:37])=[C:31]([CH:36]=3)[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[C:24]([Br:26])[N:25]=2)[CH2:17][CH2:16]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2ccccc2OCc2ccccc2)CC1
Reactant: COC(=O)c1cc(-n2cc(Br)nc(Br)c2=O)c(C)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c(C)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 111.8 %

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclopropanamine (1.026 g) in dioxane (10 mL) was treated with methyl 5-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-2-fluoro-4-methylbenzoate (Example 318d, 1.500 g) and Hunig's Base (0.936 mL) under nitrogen. The resulting solution was stirred at 100° C. for 16 h. The cooled mixture was diluted with 2 M HCl and extracted with diethyl ether. The combined organics were dried (MgSO4) and evaporated to afford the subtitle compound (2.310 g) as a foam.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[O-]CC.[Na+].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1=[CH:26]N(C)C>C(O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2[N:6]=[CH:5][N:7]=[CH:26][C:14]=2[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=CN
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ncncc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Formamidine acetate (472 mg, 4.52 mmol) in 15.0 mL of absolute ethanol was treated with sodium ethoxide (21 wt % solution in ethanol; 1.7 mL). After 30 min, a solution of the product from Step A above (1.15 g) in 8 mL of absolute ethanol was added, and the mixture was warmed at reflux for 18 h. The dark solution was cooled to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to an orange oil. Purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a light yellow gum.
Reaction SMILES: [C:1]([N:3]=[C:4]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)SC)#[N:2].O.[NH2:22][NH2:23]>C(O)C>[NH2:2][C:1]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[N:22][N:23]=1
Reactant: NN
Reactant: CSC(=NC#N)N1CCN(Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: CCO
Product: Nc1nnc(N2CCN(Cc3ccc(F)cc3)CC2)[nH]1

Procedure:
The entire portion (0.1 mole) of N-cyano-4-(p-fluorobenzyl)-1-piperazinecarboximidothioic acid, methyl ester, prepared as an oil (Example 27) was dissolved in 150 ml. of ethanol and 5.5 ml. (0.11 mole) of hydrazine hydrate were added. The mixture was refluxed for 6 hours and then evaporated to a solid residue which as crystallized from 200 ml. of ethanol, giving 21 g. of the desired product as colorless crystals, m.p. 213°-216° C. (dec.).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[NH2:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)[N:18]=1.[CH:30]([NH:33][CH2:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:43]1([CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:35][CH2:34][N:33]([CH:30]([CH3:32])[CH3:31])[C:6]([NH:13][C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=3)[N:18]=2)=[O:7])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: CC(C)NCCC(c1ccccc1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(NS(C)(=O)=O)cc2)cs1
Temperature: 25 °C
Reaction time: 40 h
Yield: 60.4 %

Procedure:
To a solution of CDI (0.163 g, 1.01 mmol) and DMAP (0.129 g, 1.06 mmol) in DMF (1 mL) at room temperature was added N-(4-(2-aminothiazol-4-yl)phenyl)methanesulfonamide 5 (0.178 g, 0.661 mmol). The reaction mixture was stirred at room temperature for 40 h and N-isopropyl-3,3-diphenylpropan-1-amine 2 (0.215 g, 0.849 mmol) was added. The reaction mixture was stirred at room temperature for 8 h and heated to 40° C. for 15 h. Direct purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in DCM) followed by purification by flash column chromatography on silica gel (eluted with 30% to 80% EtOAc in hexanes) gave 1-(3,3-diphenylpropyl)-1-isopropyl-3-(4-(4-(methylsulfonamido)-phenyl)thiazol-2-yl)urea 6 (0.219 g, 60.4% yield) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][OH:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:28][CH2:27][C:22]1[C:23]([CH3:26])=[N:24][O:25][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C:6]3([C:4]([OH:3])=[O:5])[CH2:7][CH2:8]3)=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CO)cc3)cc2)CC1
Reactant: Clc1ccccc1CBr
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1COCc1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 45, Step 2, using 1-[4′-(4-hydroxymethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-bromomethyl-2-chloro-benzene.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH2:4][N:3]1[CH:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17].Cl.[NH2:22][C@@H:23]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:24]([OH:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[CH2:39]([C@H:23]([NH:22][C:11]([C:6]1[C:5]2[CH2:4][N:3]([CH:14]([CH2:15][CH2:16][CH3:17])[CH2:18][CH2:19][CH3:20])[C:2](=[O:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:13])[C@H:24]([OH:38])[CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCC(CCC)N1Cc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(CCC)N1Cc2c(C(=O)N[C@@H](Cc3ccccc3)[C@H](O)CNCc3cccc(C(F)(F)F)c3)cccc2C1=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
136.4 mg of 1-oxo-2-(1-propylbutyl)isoindoline-4-carboxylic acid are dissolved in 8 cm3 of dichloromethane under an inert atmosphere at a temperature close to 20° C. 195 mg of ((2R,3S)-3-amino-4-phenyl-1-{[3-(trifluoromethyl)benzyl]amino}butan-2-ol hydrochloride (2:1), 9.6 mg of hydroxybenzotriazole, and 108.7 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to the solution. 0.308 cm3 of N,N-diisopropylethylamine is poured into the reaction medium. This is kept stirring for 20 h at 20° C. 10 cm3 of water are added to the reaction medium. The organic phase is washed with 10 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 310 mg of beige gum obtained are purified by flash chromatography over silica (column: 15 g; particle size: 20-40 μm, spherical; flow rate: 20 cm3/min; eluent: 95% dichloromethane/5% methanol). After concentrating the fractions under reduced pressure, 110 mg of N-[(1S,2R)-1-benzyl-2-hydroxy-3-{[3-(trifluoromethyl)benzyl]amino}propyl]-1-oxo-2-(1-propylbutyl)isoindoline-4-carboxamide are obtained in the form of a beige foam.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:15])=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[C:24](OCC)(=O)C>CN(C)C=O.C(OCC)(=O)C.CC(O)C>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:18][N:19]([CH3:21])[CH3:20])=[CH:9][C:8]=1[N:10]([CH3:24])[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(Cl)c(NS(C)(=O)=O)c1
Reactant: CCOC(C)=O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CN(C)C=CC(=O)c1ccc(Cl)c(N(C)S(C)(=O)=O)c1
Yield: 40 %

Procedure:
1.0 g (4.04 mmol) of N-(5-acetyl-2-chloro-phenyl)-methanesulfonamide were dissolved in 10 ml of dry N,N-dimethylformamide and 2.69 ml (2.41 g) (20.19 mmol) of N,N-dimethylformamide dimethylacetal. The resultant solution was refluxed for 2 hours. The solvent and the excess of volatile reagent was removed by reduced pressure distillation to yield an oil which, in the presence of ethyl acetate, gave 1.04 of a crude. It was chromatographied (silica gel) using ethyl acetate/2-propanol as eluent. 0.51 g of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-N-methyl-methanesulfonamide as a yellowish-white solid were obtained (yield 40%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:14][F:15])=[N:8][N:9]([CH3:13])[C:10]=1[CH2:11][F:12])=[O:5])C.[OH-].[Na+]>C(O)C>[CH3:13][N:9]1[C:10]([CH2:11][F:12])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH2:14][F:15])=[N:8]1
Reactant: CCOC(=O)c1c(CF)nn(C)c1CF
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(CF)c(C(=O)O)c1CF
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid ethyl ester (0.5 g, 2.0 mmol) in ethanol (3 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (0.8 ml) and stirred at room temperature for 2 h. The solvent was removed by rotary evaporation; the residue was taken up in water (10 ml) and extracted with diethyl ether (10 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×10 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Methyl-3,5-difluoromethyl-4-pyrazolecarboxylic acid (0.44 g, 1.95 mmol, 97%) was isolated as a colourless solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:21])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[CH2:12][C:11](=[N:18]O)[C:10]2=[O:20])=[O:6].C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1>O>[C:11]([CH2:12][C:13]1[C:9]([C:10]([OH:20])=[O:29])=[CH:8][C:7]([C:5]([N:4]([CH3:3])[CH3:21])=[O:6])=[C:15]([O:16][CH3:17])[CH:14]=1)#[N:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1C(=O)N(C)C)C(=O)C(=NO)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)cc1C(=O)N(C)C
Temperature: 50 °C
Yield: 89.3 %

Procedure:
To a solution of NaOH (1.6 g, 40.54 mmol) in H2O (30 ml) was added of 2-Hydroxyimino-6-methoxy-3-oxo-indan-5-carboxylic acid dimethylamide (2.8 g, 10.67 mmol). The mixture was heated at 50° C. Then p-Toluenesulfonyl chloride (5.7 g, 30 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product (2.5 g, 89.28%). LC-MS: m/e 261 (M−1).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)[C:3]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:26]([O:25][C:23]([C:3]1[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:8]2)=[CH:5][S:6][C:2]=1[NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][CH:46]=[C:38]([F:37])[CH:39]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1N
Reactant: O=C(Cl)c1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C2CCCN(C(=O)OCc3ccccc3)C2)csc1NC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 55 (˜2 mmol) in DCM (10 ml) was added DIEA (0.7 ml, 4 mmol), 3-fluorobenzoyl chloride (0.48 ml, 4 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 17 hrs, diluted with DCM (50 ml), washed with water, saturated sodium bicarbonate (aq.), water, 1N HCl (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum. The crude product was purified on a silica gel column to give 56 as a yellow oil (0.48 g). LC-MS for C27H27FN2O5S: 510; found: 511.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.O>C(#N)C>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1)=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2oncc2CCCO)cc1
Solvent: CC#N
Solvent: O
Product: CS(=O)c1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol (900 mg) in acetonitrile (20 ml) was gradually added m-chloroperbenzoic acid (750 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and crystals (390 mg, yield 41%) of 3-[5-(4-methylsulfinylphenyl)-4-isoxazolyl]propan-1-ol were obtained from a fraction eluted with acetone-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-diethyl ether to give a colorless prism. melting point: 73–74° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To an ice-cold solution of N-Boc-4-piperidine-ethanol (5.0 g, 21.8 mmol) and Et3N (4.6 mL, 33.0 mmol) in dry DCM (10 mL) was added p-toluenesulfonyl chloride (6.25 g, 32.8 mmol) slowly. Upon addition, the reaction was warmed to room temperature and stirred for 20 h. The reaction mixture was washed with water (40 mL), 10% (wt/v) citric acid(aq) (40 mL), and saturated NaHCO3(aq) (40 mL). The DCM layer was dried with MgSO4, filtered and concentrated in vacuo to give a pale yellow oil, which was chromatographed to give the title compound (7.47 g, 89% yield) as a clear and colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[S]Cl.[C:11](=[S:13])=[S:12]>C(O)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:11]([SH:13])[S:12][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1ccc(Cl)cc1
Agent: [S]Cl
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Sc1nc2ccc(Cl)cc2s1
Temperature: 60 °C

Procedure:
To a stirred solution of 4-chloroaniline (2.55 g) in acetic acid (5 cm3) was added sulphur monochloride (10 cm3) causing formation of a thick red slurry. The reaction was heated at 60° C. for 4 hours giving a mixture of green solid and a green solution. The mixture was diluted with hexane and the green solid was filtered off. The solid was taken into water and 2M NaOH was added and the mixture heated for 4 hours at 100° C. and then filtered through celite to give a pale pink filtrate. Carbon disulphide (2 cm3) was added to the filtrate and the reaction was heated at reflux for 15 hours. The mixture was cooled and acidlied to pH 1 causing formation of a thick yellow precipitate. Filtration and recrystallisation from ethanol/acetone/water gave 6-chloro-2-mercaptobenzthiazole as a white solid. 1H NMR (DMSO): d 7.97 (1H, d), 7.58 (1H, dd), 7.41 (1 H, d). Mp 251°-253° C. (dec).